Penzes, Peter, PhD

Current Research

Current Research

Signal transduction mechanisms regulating the development and structural plasticity of excitatory synapses

Experience-dependent and independent alterations of the strength and structure of individual synapses contribute to the formation of neural circuits and underlie storage and processing of information in the brain. These functional and structural changes of synapses, collectively referred to as synaptic plasticity , are essential for many aspects of behavior, including learning and memory.

Dendritic spines are tiny protrusions of dendrites and are the sites of most excitatory synapses in the brain. Spines represent the postsynaptic compartment of excitatory synapses and contain the machinery required for plasticity. Changes in the number, structure, and protein composition of spines, in the developing and adult brain have been of great interest recently because they are thought to be essential for brain wiring, neural circuit refinement, and experience-dependent plasticity. Moreover, defects of spine plasticity are associated with mental retardation, drug addiction, neurological disorders and mental illness.

We are interested in the molecular mechanisms that regulate the development and structural plasticity of excitatory synapses. We focus on signal transduction pathways which link synaptic receptors, such as those for neurotransmitters (glutamate, serotonin, dopamine), trans-synaptic signaling and adhesion molecules (ephrins and their Eph receptors, cadherins), and growth factors, to the actin cytoskeleton. Key players in these mechanisms are small GTPases related to Ras. We have previously shown that signaling proteins such as the brain-specific guanine-nucleotide exchange factor kalirin , an activator of Rac1 GTPase, B-type ephrins and their EphB receptors, PAK kinase, small GTPase Rap and the PDZ domain-containing protein AF-6/afadin are regulators of dendritic spine morphogenesis and structural plasticity.

We are interested in discovering novel synaptic signaling mechanisms, in evaluating their role in controlling neuronal form and function, neural circuit formation and function, and behavior and cognition.

We employ molecular, biochemical and cell biological methods, confocal microscopy and time-lapse imaging of neurons, and genetic approaches to identify and characterize novel molecular mechanisms of synapse development and structural plasticity. Such mechanisms are also likely to be associated with neuropsychiatric disorders (schizophrenia, depression, Alzheimer's disease, eplilepsy, HIV encephalitis) and neurodevelopmental disorders (mental retardation, autism, Rett syndrome, Down syndrome), drug addiction, and could yield potential targets for treatments of these conditions.

<strong>Collaborations</strong>

We expect that these signaling pathways also affect the electrophysiological properties of neurons. Hence we seek collaborations with labs interested in analyzing the physiological effects of these molecules on neurons.